Pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor lumiracoxib in the lipopolysaccharide-stimulated rat air pouch model.

Abstract Purpose: To investigate the pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor, lumiracoxib, in the rat air pouch. Methods: Air pouches were injected with lipopolysaccharide to stimulate prostaglandin E 2 (PGE 2 ) production 1 h after lumiracoxib treatment. Pouch fluid samples were collected 6 or 24 h after lumiracoxib administration to measure PGE 2 levels. Lumiracoxib concentrations in pouch fluid and plasma were measured by mass spectrometry. Results: Oral administration of lumiracoxib resulted in dose-dependent inhibition of PGE 2 production 6 and 24 h post-dose. The estimated ED 50 values for inhibition of PGE 2 production were 0.1 and 2.0 mg/kg at 6 and 24 h, respectively. Lumiracoxib concentrations in plasma and pouch fluid increased in proportion to dose. There was a strong positive correlation between lumiracoxib concentrations in plasma and pouch fluid compartments. Lumiracoxib concentrations were higher in plasma than in pouch fluid 6 h post-dose, but at 24 h post-dose, pouch fluid concentrations were ≥4-fold greater than plasma concentrations. Conclusions: Lumiracoxib readily enters the air pouch and persists in this extravascular compartment for a longer period of time than in plasma. This distribution profile may contribute to the ability of lumiracoxib to inhibit PGE 2 production up to 24 h after dosing.